Regulation and role of IL-7 production in HIV-1 infection

<p>The concentration of interleukin-7 (IL-7) in human serum is elevated in various clinical conditions associated with lymphopenia, including HIV-1 infection. IL-7 is an essential factor for T cell differentiation and survival, and it was suggested that high serum IL-7 concentration may represent a homeostatic response to T cell depletion, which may promote T cell regeneration.</p><p>In order to increase our understanding on the regulation of IL-7 production, we investigated specimens from HIV-1 infected patients during chronic infection and in long term non-progressors (LTNPs). Serum IL-7 levels correlated with T-cell depletion in HIV-1 infected individuals. In some patients, we observed that serum IL-7 decreased upon progression to AIDS, suggesting a role for IL-7 in T-cell maintenance in sporadic cases. Interestingly, IL-7 levels were significantly lower in stable LTNPs than in patients who lost the LTNP status in a 3-year follow-up (P<0.001), indicating that serum IL-7 concentration might be a valuable marker for maintenance of the LTNP status.</p><p>The number of CD8+CD28- T cells increases significantly during aging and during HIV-1 infection. These cells have a reduced expression of the IL-7 receptor alpha (IL-7Rα), as compared to CD8+CD28+ T cells. As CD8+CD28- T cells have been associated with dendritic and T cell suppression, we analyzed whether an increase in CD8+CD28- T cell numbers during HIV-1 infection could lead to impaired T cell responses. Peripheral blood CD8+CD28- T cells of both HIV-infected and non-infected individuals promoted dendritic cell activation. The CD8+CD28- T cell accumulation during HIV-1 infection may thus contribute to inflammatory reactions and immune activation.</p><p>Stromal cells and intestinal epithelial cells are known to produce IL-7. The mechanisms and cellular factors regulating IL-7 production are still unclear. We assessed whether IL-1β and IFN- γ, cytokines produced during inflammatory conditions, may impact on IL-7 production. We used human intestinal epithelial cells (DLD-1 cell line) and bone marrow stromal cells (HS27 cell line) to evaluate IL-7 production at the mRNA and protein levels. To assess whether treatment of HS27 cells with IL-1 and/or IFN-γ leads to changes in the gene expression of cytokines, Toll-like receptors (TLRs) and chemokines, we analysed gene expression profiles using the whole-genome microarray Human Gene 1.0 ST. We found that IFN-γ enhanced the expression of IL-7 protein and mRNA (P<0.001) in both cell lines. IL-1 treatment led to a significant down-regulation (P<0.001) of IL-7 mRNA expression in both cell lines. The gene profiles revealed dramatic changes in expression of cytokines and their receptors, of IFN regulatory factors (IRF-1 and 2) and of important chemo-attractants for T cells. The microarray results were verified by additional methods. Our results were discussed in the setting of inflammation and T-cell survival in the gut compartment during HIV-1 infection where stromal and epithelial cells may produce factors that contribute to impaired IL-7 homeostasis and homing of T cells.</p><p>It was previously reported that IL-7 might stimulate T cell activation and CD95 mediated T cell apoptosis. HIV-1 infection leads to B cell abnormalities including increased apoptosis via the CD95 death receptor pathway and loss of memory B cells. Here we present a novel mechanism that can lead to increased B cell apoptosis in the presence of high IL-7 concentration. T cells cultured with IL-7 induced high CD95 expression on resting B cells together with an increased sensitivity to CD95 mediated apoptosis. As the mediator molecule responsible for B cell priming to CD95 mediated apoptosis we identified the cytokine IFN-γ that T cells secreted in response to IL-7. In the serum of HIV-1 infected individuals IL-7 and IFN-γ levels were in correlation and the level of both cytokines correlated with CD95 expression on circulating B lymphocytes in non-viremic individuals. These results indicate a potential link between IL-7 and the increased B cell apoptosis observed in HIV-1 infected individuals.</p><p>In conclusion the results presented in this PhD thesis highlight mechanisms of regulation of IL-7 production dependent on the number of circulating T cells and on the exposure of IL-7 producing cells to high levels of inflammatory cytokines. We also present data on the role of IL-7 in regulating CD95 expression and CD95 mediated apoptosis on B cells through IFN-γ produced by T cells; the impact of this finding on the outcome of IL-7 therapy during HIV-1 infection will be verified by ongoing clinical studies.</p><h3>List of scientific papers</h3><p>I. Fluur C, Rethi B, Thang PH, Vivar N, Mowafi F, Lopalco L, Foppa CU, Karlsson A, Tambussi G, Chiodi F. Relationship between serum IL-7 concentrations and lymphopenia upon different levels of HIV immune control. AIDS. 2007 May 11;21(8):1048-50. <br><a href="https://doi.org/10.1097/QAD.0b013e32810c8caa">https://doi.org/10.1097/QAD.0b013e32810c8caa</a><br><br> </p><p>II. Vivar N, Thang PH, Atlas A, Chiodi F, Rethi B. Potential role of CD8+CD28-T lymphocytes in immune activation during HIV-1 infection. AIDS. 2008 May 31;22(9):1083-6. <br><a href="https://doi.org/10.1097/QAD.0b013e3282fce613">https://doi.org/10.1097/QAD.0b013e3282fce613</a><br><br> </p><p>III. Thang PH, Ruffin N, Brodin D, Rethi B, Cam PD, Hien NT, Lopalco L, Vivar N, Chiodi F. The role of IL-1beta in reduced IL-7 production by stromal and epithelial cells: a model for impaired T-cell numbers in the gut during HIV-1 infection. J Intern Med. 2010 Aug;268(2):181-93. <br><a href="https://doi.org/10.1111/j.1365-2796.2010.02241.x">https://doi.org/10.1111/j.1365-2796.2010.02241.x</a><br><br> </p><p>IV. Sammicheli S, Thang PH*, Dang VPL*, Ruffin R, Pensieroso P, Vivar N, Hejdeman B, Chiodi F and Rethi B. IL-7 promotes CD95-induced apoptosis in B cells via the IFN-γ/STAT1 pathway. [Submitted]</p>